A High-Frequency Regulatory Polymorphism in the p53 Pathway Accelerates Tumor Development

Abstract

Summary MDM2, a negative regulator of p53, is elevated in many cancers that retain wild-type p53. A single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the affinity of Sp1 resulting in elevated MDM2 levels. We generated mice carrying either the MDM2SNP309T or the MDM2SNP309G allele to address the impact of MDM2SNP309G on tumorigenesis. Mdm2SNP309G/G cells exhibit elevated Mdm2 levels, reduced p53 levels, and decreased apoptosis. Importantly, some Mdm2SNP309G/G mice succumbed to tumors before one year of age, suggesting that this allele increases tumor risk. Additionally, the Mdm2SNP309G allele potentiates the tumor phenotype and alters tumor spectrum in mice inheriting a p53 hot-spot mutation. These data provide causal evidence for increased cancer risk in carriers of the Mdm2SNP309G allele.

Characterization of cancer-associated missense mutations in MDM2

“…It is worth noting that the SNP309G polymorphism in the MDM2 promoter modestly increases MDM2 mRNA levels (approximately 2 fold) and is associated with an increased risk for development of cancer. [31][32][33][34] Further in vivo studies using genetically engineered mice carrying one of these point mutations may determine whether, like SNP309G, these mutations can promote tumor development. Taken together, our data provide novel insights into the functional impact of cancer-associated mutations in MDM2 and suggest that these genetic changes in human cancers may not be neutral events.…”

“…34 This increased growth rate has been attributed to decreased p53 levels due to high turnover. 34 Since some of the MDM2 mutants did not promote p53 degradation, we assessed whether they were still able to increase cell proliferation. We generated stable cell lines of U2OS osteosarcoma cells expressing either wild-type or mutant forms of MDM2 (Fig.…”

“…[31][32][33][34] Mouse embryonic fibroblasts derived from mice carrying humanized MDM2 SNP309G alleles express higher levels of MDM2 protein and grow faster than their wild-type counterparts. 34 This increased growth rate has been attributed to decreased p53 levels due to high turnover. 34 Since some of the MDM2 mutants did not promote p53 degradation, we assessed whether they were still able to increase cell proliferation.…”

p53: Point Mutations, SNPs and Cancer

“…Cancer-related SNPs in regulators of p53. Summarized data for SNPs in Mdm2 (Bond et al, 2004;Bond and Levine, 2007;Post et al, 2010), Mdm4 (Wynendaele et al, 2010), ATM (Barrett et al, 2011;Jones et al, 2005;Maillet et al, 1999;Thorstenson et al, 2001), NQO1 (Asher andShaul, 2005;Jamieson et al, 2007;Ross and Siegel, 2004 Table 3. Cancer-related SNPs in p53 target genes.…”

The Regulation of Aging and Longevity: A New and Complex Role of p53

“…104,105 SNP309 has been shown to be associated with increased risk for cancer in both humans and SNP309 knock-in mice. 104,106 It will be of interest to study whether SNP309 affects the life span in human populations and whether p53 codon 72 SNP and SNP309 have a combinatory effect on human life span.…”